Antidepressant (3-aryl-2,3-dihydrobenzofuran-3-yl)alkylamines

ABSTRACT

There are described compounds of the formula ##STR1## where n is 2 or 3, X and Y are each independently hydrogen, loweralkyl, or halogen, and R 1  and R 2  are each independently hydrogen, loweralkyl, cyano, beta,beta,beta-trichloroethyoxycarbonyl, cyclopropylmethyl, phenethyl, or cyanoethyl, but at least one of the two is loweralkyl, which are useful as antidepressant and analgesic agents; novel intermediate compounds for preparing said compounds; and methods for synthesizing the foregoing compounds.

This invention relates to compounds of the formula ##STR2## where n is 2or 3, X and Y are each independently hydrogen, loweralkyl, or halogen,and R₁ and R₂ are each independently hydrogen, loweralkyl, cyano,beta,beta,beta-trichloroethyoxycarbonyl, cyclopropylmethyl, phenethyl,or cyanoethyl, but at least one of the two is loweralkyl, or apharmaceutically acceptable acid addition salt thereof, which are usefulas antidepressant and analgesic agents, antidepressant compositionscomprising an effective depression alleviating amount of a compound ofFormula I; and analgesic composition comprising an effective amount of acompound of Formula I.

This invention also relates to compounds of the formula ##STR3## where nis 2 or 3, X and Y are each independently hydrogen, loweralkyl orhalogen, and R' is loweralkyl which are useful as intermediates forsynthesizing compounds of Formula I.

This invention also relates to compounds of the formula ##STR4## where Xand Y are each independently hydrogen, loweralkyl or halogen, and R ishydrogen or --(CH₂)_(n) N(R')₂, n being 2 or 3 and R' being loweralkylwhich are useful as intermediates for synthesizing compounds of FormulaII.

This invention also relates to methods of synthesizing the foregoingcompounds of Formulas I, II and III.

To the best of our knowledge the compounds of the present invention havenot been described or suggested.

Throughout the specification and appended claims, the term "loweralkyl"shall mean an alkyl group having 1-4 carbon atoms. The term "halogen"shall mean fluorine, chlorine, bromine or iodine unless otherwiseindicated.

The compounds of this invention can be prepared by following one or moreof the steps described below. Throughout the description of thesynthetic steps, the definitions of n, X, Y, R₁, R₂, R and R' are asgiven above unless otherwise indicated.

STEP A

Compound VI below is prepared by reacting Compound IV with Compound V ina suitable solvent such as dry THF. ##STR5##

Compound IV is readily available or synthesizable by known methods. Forinstance, where X is 5-chloro in Formula IV, it can be prepared byreacting o-anisaldehyde with N-chlorosuccimide in a suitable solventsuch as DMF. A typical reaction condition is stirring at 60° C. for 20hours.

Compound V can be prepared in situ by reacting, for instance, CompoundVII with n-BuLi in a suitable solvent such as THF. A typical ##STR6##reaction condition is adding a suitable solution of n-BuLi (such ashexane solution) at a low temperature (e.g. -60° C.) under nitrogen andstirring the mixture for a few hours.

After Compound V has been prepared in situ as described above, asuitable solution of Compound IV (e.g. THF solution) is added to theabove mixture and the mixture is stirred, for instance, at roomtemperature overnight to obtain Compound VI.

STEP B

As an alternative to STEP A, Compound VI can be prepared by using aGrignard reagent of Formula VIII instead of Compound V. ##STR7## SaidGrignard synthesis is conducted in a routine manner in a suitablesolvent such as anhydrous ethyl ether.

STEP C

Compound VI is chlorinated to Compound IX by use of, for instance,thionyl chloride in a suitable solvent such as chloroform ordichloromethane. A typical reaction condition is refluxing the mixturefor a few hours. ##STR8##

STEP D

Compound IX is reacted with AgCN in a suitable solvent such as dry CH₃CN to afford Compound X. A typical reaction condition is refluxing themixture for 5-30 hours. ##STR9##

STEP E

Where the oxime compound of Formula XI below is readily available orsynthesizable as in the case of X=Y=hydrogen in said formula, Compound Xcan also be obtained, instead of following the above STEPS A through D,by reacting Compound XI with trifluoroacetic anhydride, for instance, ina suitable solvent such as dichloromethane. A typical reaction conditionis stirring the reaction mixture at room temperature for a few hours.##STR10##

STEP F

Compound of Formula IIIa below is obtained by reacting Compound X with acompound of Formula XII where Hal is chlorine or bromine and n is 2 or3. ##STR11## Said reaction is conducted with the aid of a strong basesuch as LiN(i-Pr)₂. Said lithium compound is prepared in situ, forinstance, by reacting n-BuLi with di-isopropylamine in a suitablesolvent. Thus, said synthesis of Compound IIIa is conducted typically asfollows.

A solution of n-BuLi in hexane is added to a solution ofdi-isopropylamine in dry THF at -70° C. under nitrogen and the mixtureis stirred for 15 minutes and then brought to -30°. A solution ofCompound X in THF is added to the above mixture and the resultantmixture is stirred at 0°-30° C. for less than 1 hour. Compound XII isadded dropwise to the resultant mixture at 0° C. and the mixture isthereafter stirred at room temperature for a short period of time (e.g.15 minutes) and then at reflux for a few hours to obtain Compound IIIa.

STEP G

Compound IIIa is cyclized in a strongly acidic medium such as 48% HBr toafford Compound XIII. A typical reaction condition is stirring themixture at 100° C. for 40 hours. ##STR12##

STEP H

Compound XIII is subjected to hydride reduction to afford Compound IIaby use of, for instance, LiAlH₄ in a suitable solvent such as anhydrousethyl ether. A typical reaction condition is stirring the reactionmixture at 0°-30° C. for 1-3 hours. ##STR13##

STEP I

Compound IIa is cyclized to afford Compound Ia by reacting it, forinstance, with a mixture of methanesulfonyl chloride and triethylaminein a suitable solvent such as dichloromethane. A typical reactioncondition is stirring the mixture at 0°-30° C. for a few hours.##STR14##

STEP J

Compound Ia is reacted with cyanogen bromide or chloride, preferablybromide, in a suitable solvent such as chloroform to afford CompoundXIV. A typical reaction condition is refluxing the mixture for severalhours. ##STR15##

STEP K

Compound Ia is reacted with beta,beta,beta-trichloroethyl chloroformatein a suitable solvent such as dichloromethane in the presence of an acidscavenger such as K₂ CO₃ to afford Compound XV. A typical reactioncondition is stirring the mixture at room temperature overnight.##STR16##

STEP L

Compound XV is reacted with zinc and glacial acetic acid to affordCompound XVI. Typically, activated zinc is added in small portions to asolution of Compound XV in glacial acetic acid and the mixture stirredat room temperature for a few hours. ##STR17##

STEP M

Compound XVI is reacted with cyclopropylmethyl chloride in a suitablesolvent such as DMF in the presence of an acid scavenger such as K₂ CO₃and a reaction initiator such as KI to afford Compound XVII. A typicalreaction condition is stirring the mixture at 65° C. for several hours.##STR18##

STEP N

As an alternative to STEP M, Compound XVI may first be reacted withcyclopropanecarboxylic acid chloride to obtain the corresponding amide,and the the amide may be reduced to afford Compound XVII above. Thefirst step (amidation) is conducted, for instance, in dichloromethane inthe presence of pyridine and stirring the mixture at room temperatureovernight. The second step (reduction) is conducted, for instance, byreacting the amide with LiAlH₄ in a suitable solvent such as dry THF andstirring the mixture at room temperature for about 1 hour. ##STR19##

STEP O

Compound XVI is reacted with phenethyl bromide to afford Compound XVII.Said alkylation reaction is conducted, for instance, in DMF in thepresence of K₂ CO₃ and KI, and stirring the mixture at 80° C. for 4hours. ##STR20##

STEP P

Compound XVI is reacted with acrylonitrile to afford Compound XIX. Saidreaction is conducted, for instance, by using an excess amount ofacrylonitrile and stirring the mixture of the two reactants at roomtemperature for a few hours and then at 75° C. for a few hours.##STR21##

It will be noticed that the foregoing STEPS A through P are directed tothe synthesis of Compounds I where at least one of R₁ or R₂ is methyl,to the synthesis of Compounds II where R' is methyl and to the synthesisof Compounds III where R is hydrogen or --(CH₂) _(n) NMe₂. However, itwill be apparent from the foregoing descriptions of the synthetic schemethat the remaining compounds covered by Formulas I, II and III can beprepared in a similar manner by using a compound of the formulaHal--(CH₂)_(n) N(R₃)₂ where R₃ is an alkyl group of 2-4 carbon atomsinstead of Compound XII in STEP F and following the subsequent STEPS Gthrough P.

All other starting materials shown above are either known compounds oreasily prepared by routine methods known to the art from readilyavailable materials.

Compounds I of the present invention are useful as antidepressant agentsdue to their ability to prevent Tetrabenazine induced ptosis in mice.The method used is as follows.

Male mice weighing 20 to 30 grams are used in test groups of fivesubjects. All compounds are dissolved, or suspended with one drop of anon-ionic surfactant in distilled water and administered in volumes of10 ml/kg of body weight. Tetrabenazine (TBZ) solution is made frommethanesulfonate salt and the concentration is adjusted to enable theadministration of 40 mg/kg of base by intraperitoneal injection (i.p.).

If the test compound is administered intraperitoneally, TBZ is injected30 minutes after administration. If the test compound is administeredorally (p.o.), TBZ is injected 60 minutes after the administration. Acontrol group receives solvent and TBZ by the same route and at the sameintervals as the drug groups.

Thirty and sixty minutes after TBZ injection the subjects are placed inindividual plastic containers (101/2"×8"×6") and one minute aftertransfer they are scored for ptosis on the following scale: eyesclosed=4, eyes 3/4 closed=3, eyes 1/2 closed=2, eyes 1/4 closed=1, andeyes open=0. The total score for each group of five will therefore befrom 0 to 20 and these scores are used as indications of drug activity.

The vehicle-control group score is used as a determinate of the validityof each test. If the control score is less than 17, the results arediscarded and the test repeated.

For ED₅₀ estimation, four or five doses are administered in order tobracket the estimated value and only vehicle-control scores of 17 to 20are accepted to assure the accuracy of the ED₅₀ estimate. Alinear-regression analysis is used to estimate ED₅₀ values. Results ofthe antidepressant activities of some of the compounds of this inventionare shown in Table 1.

The compounds of the invention compare favorably with the well knownantidepressant compound imipramine, which, in a similar test exhibitedan antidepressant ED₅₀ =5.5 mg/kg, orally.

Compounds I of the present invention are also useful as analgesic agentsdue to their ability to alleviate pain in mammals. The activity of thecompounds is demonstrated in the 2-phenyl-1,4-benzoquinone-inducedwrithing test in mice, a standard assay for analgesia, [Proc. Soc.Exptl. Biol. Med., 95, 729 (1957)]. Results of the analgesic activitiesof some of the compounds of this invention are shown in Table 1.

The compounds of the invention compare favorably with the well knownanalgesic compound ibuprofen, which, in a similar test exhibited ananalgesic ED₅₀ =10.4 mg/kg, orally.

                                      TABLE 1                                     __________________________________________________________________________                     TBZ         PQW                                                                    Percent     Percent                                                           ptosis      writhing                                                          inhit. @    inhib. @                                                          20 mg/kg    10 mg/kg                                                     ED.sub.50 i.p.                                                                     i.p.   ED.sub.50 s.c.                                                                     s.c.                                        __________________________________________________________________________    2-(3-Phenyl-2,3- 3.03.sup.a        49.sup.b                                   dihydrobenzofuran-3-yl)-N,N--                                                 dimethylethylamine oxalate                                                    2-(3-Phenyl-2,3-      20          59                                          dihydrobenzofuran-3-yl)-N--                                                   cyano-N--methylethylamine                                                     2-(3-Phenyl-2,3-       6                                                      dihydrobenzofuran-3-yl)-N--                                                   (2,2,2-trichloroethoxycarbonyl)-                                              N--methylethylamine                                                           2-(3-Phenyl-2,3- 4.99.sup.a       53                                          dihydrobenzofuran-3-yl)-N--                                                   methylethylamine hydrochloride                                                2-(3-Phenyl-2,3-      22     6.27                                             dihydrobenzofuran-3-yl)-N--                                                   cyclopropylmethyl-N--                                                         methylethylamine fumarate                                                     2-(3-Phenyl-2,3-      17     20                                               dihydrobenzofuran-3-yl)-N--                                                   methyl-N--phenethylethylamine                                                 fumarate                                                                      2-(3-Phenyl-2,3-      21           33.sup.b                                   dihydrobenzofuran-3-yl)-N--                                                   (2-cyanoethyl)-N--                                                            methylethylamine oxalate                                                      3-(3-Phenyl-2,3-      37           59.sup.c                                   dihydrobenzofuran-3-yl)-N,N--                                                 dimethylpropylamine oxalate                                                   3-(3-Phenyl-2,3-                  32                                          dihydrobenzofuran-3-yl)-N--                                                   (2,2,2-trichloroethoxycarbonyl)-                                              N--methylpropylamine                                                          3-(3-Phenyl-2,3- 13.68            54                                          dihydrobenzofuran-3-yl)-N--                                                   methylpropylamine hydrochloride                                               3-(3-Phenyl-2,3-       0          46                                          dihydrobenzofuran-3-yl)-N--                                                   methyl-N--phenethylpropylamine                                                oxalate                                                                       3-(3-Phenyl-2,3-      10          48                                          dihydrobenzofuran-3-yl)-N--                                                   cyclopropylmethyl-N--                                                         methylpropylamine oxalate                                                     3-(3-Phenyl-5-chloro-2,3-                                                                           15           38.sup.b                                   dihydrobenzofuran-3-yl)-N,N--                                                 dimethylpropylamine oxalate                                                   3-[3-(4-Tolyl)-2,3-   20          61                                          dihydrobenzofuran-3-yl]-N,N--                                                 dimethylethylamine fumarate                                                   3-[3-(2-Tolyl)-2,3-   10          34                                          dihydrobenzofuran-3-yl]-N,N--                                                 dimethylethylamine fumarate                                                   3-[3-(2-Fluorophenyl)-2,3-                                                                          60          35                                          dihydrobenzofuran-3-yl]-N,N--                                                 dimethylethylamine fumarate                                                   __________________________________________________________________________     a: determined by oral administration                                          b: at 20 mg/kg                                                                c: at 25 mg/kg                                                           

Effective quantities of the compounds of the invention may beadministered to a patient by any of the various methods, for example,orally as in capsules or tablets, parenterally in the form of sterilesolutions or suspensions, and in some cases intravenously in the form ofsterile solutions. The free base final products, while effectivethemselves, may be formulated and administered in the form of theirpharmaceutically acceptable acid addition salts for purposes ofstability, convenience of crystallization, increased solubility and thelike.

Acids useful for preparing the pharmaceutically acceptable acid additionsalts of the invention include inorganic acids such as hydrochloric,hydrobromic, sulfuric, nitric, phosphoric and perchloric acids, as wellas organic acids such as tartaric, citric, acetic, succinic, maleic,fumaric and oxalic acids.

The active compounds of the present invention may be orallyadministered, for example, with an inert diluent or with an ediblecarrier, or they may be enclosed in gelatin capsules, or they may becompressed into tablets. For the purpose of oral therapeuticadministration, the active compounds of the invention may beincorporated with excipients and used in the form of tablets, troches,capsules, elixirs, suspensions, syrups, wafers, chewing gum and thelike. These preparations should contain at least 0.5% of activecompound, but may be varied depending upon the particular form and mayconveniently be between 4% to about 70% of the weight of the unit. Theamount of active compound in such compositions is such that a suitabledosage will be obtained. Preferred compositions and preparationsaccording to the present invention are prepared so that an oral dosageunit form contains between 1.0-300 milligrams of active compound.

The tablets, pills, capsules, troches and the like may also contain thefollowing ingredients: a binder such as micro-crystalline cellulose, gumtragacanth or gelatin; an excipient such as starch or lactose, adisintegrating agent such as alginic acid, Primogel, cornstarch and thelike; a lubricant such as magnesium stearate or Sterotex; a glidant suchas colloidal silicon dioxide; and a sweetening agent such as sucrose orsaccharin may be added or a flavoring agent such as peppermint, methylsalicylate, or orange flavoring. When the dosage unit form is a capsule,it may contain, in addition to materials of the above type, a liquidcarrier such as a fatty oil. Other dosage unit forms may contain othervarious materials which modify the physical form of the dosage unit, forexample, as coatings. Thus tablets or pills may be coated with sugar,shellac, or other enteric coating agents. A syrup may contain, inaddition to the active compounds, sucrose as a sweetening agent andcertain preservatives, dyes, colorings and flavors. Materials used inpreparing these various compositions should be pharmaceutically pure andnon-toxic in the amounts used.

For the purposes of parenteral therapeutic administration, the activecompounds of the invention may be incorporated into a solution orsuspension. These preparations should contain at least 0.1% of activecompound, but may be varied to be between 0.5 and about 30% of theweight thereof. The amount of active compound in such compositions issuch that a suitable dosage will be obtained. Preferred compositions andpreparations according to the present invention are prepared so that aparenteral dosage unit contains between 0.5 to 100 milligrams of activecompound.

The solutions or suspension may also include the following components: asterile diluent such as water for injection, saline solution, fixedoils, polyethylene glycols, glycerine, propylene glycol or othersynthetic solvents; antibacterial agents such as benzyl alcohol ormethyl parabens; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylenediaminetetraacetic acid; buffers suchas acetates, citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose. The parenteral preparationcan be enclosed in disposable syringes or multiple dose vials made ofglass or plastic.

Examples of the compounds of this invention include:

2-(3-Phenyl-2,3-dihydrobenzofuran-3-yl)-N,N-dimethylethylamine oxalate;

2-(3-Phenyl-2,3-dihydrobenzofuran-3-yl)-N-cyano-N-methylethylamine;

2-(3-Phenyl-2,3-dihydrobenzofuran-3-yl)-N-(2,2,2-trichloroethoxycarbonyl)-N-methylethylamine;

2-(3-Phenyl-2,3-dihydrobenzofuran-3-yl)-N-methylethylamine hydrochloride

2-(3-Phenyl-2,3-dihydrobenzofuran-3-yl)-N-cyclopropylmethyl-N-methylethylaminefumarate;

2-(3-Phenyl-2,3-dihydrobenzofuran-3-yl)-N-methyl-N-phenethylethylaminefumarate;

2-(3-Phenyl-2,3-dihydrobenzofuran-3-yl)-N-(2-cyanoethyl)-N-methylethylamineoxalate;

3-(3-Phenyl-2,3-dihydrobenzofuran-3-yl)-N,N-dimethylpropylamine oxalate;

3-(3-Phenyl-2,3-dihydrobenzofuran-3-yl)-N-(2,2,2-trichloroethoxycarbonyl)-N-methylpropylamine;

3-(3-Phenyl-2,3-dihydrobenzofuran-3-yl)-N-methylpropylaminehydrochloride;

3-(3-Phenyl-2,3-dihydrobenzofuran-3-yl)-N-methyl-N-phenethylpropylamineoxalate;

3-(3-Phenyl-2,3-dihydrobenzofuran-3-yl)-N-cyclopropylmethyl-N-methylpropylamineoxalate;

3-(3-Phenyl-5-chloro-2,3-dihydrobenzofuran-3-yl)-N,N-dimethylpropylamineoxalate;

3-[3-(4-Tolyl)-2,3-dihydrobenzofuran-3-yl]-N,N-dimethylethylaminefumarate;

3-[3-(2-Tolyl)-2,3-dihydrobenzofuran-3-yl]-N,N-dimethylethylaminefumarate;

3-[3-(2-Fluorophenyl)-2,3-dihydrobenzofuran-3-yl]-N,N-dimethylethylaminehydrochloride;

alpha-(2-Methoxyphenyl)phenylacetonitrile;

4-Dimethylamino-2-(2-methoxyphenyl)-2-phenylbutyronitrile oxalate;

5-Dimethylamino-2-(2-methoxyphenyl)-2-phenylvaleronitrile hydrochloride;

alpha-(5-Chloro-2-methoxyphenyl)phenylacetonitrile;

5-Dimethylamino-2-(5-chloro-2-methoxyphenyl)-2-phenylvaleronitrileoxalate;

alpha-(2-Methoxyphenyl)-4-tolylacetonitrile;

alpha-(2-Methoxyphenyl)-2-tolylacetonitrile;

4-Dimethylamino-2-(2-methoxyphenyl)-2-(4-tolyl)butyronitrile maleate;

4-Dimethylamino-2-(2-methoxyphenyl)-2-(2-tolyl)butyronitrile maleate;

alpha-(2-Methoxyphenyl)-2-fluorophenylacetonitrile;

4-Dimethylamino-2-(2-fluorophenyl)-2-(2-methoxyphenyl)butyronitrilefumarate;

4-Dimethylamino-2-(2-hydroxyphenyl)-2-phenylbutanol hydrochloride;

5-Dimethylamino-2-(2-hydroxyphenyl)-2-phenylpentanol oxalate;

5-Dimethylamino-2-(5-Chloro-2-hydroxyphenyl)-2-phenylpentanol oxalate;

4-Dimethylamino-2-(2-hydroxyphenyl)-2-(2-tolyl)butanol hydrochloride;

4-Dimethylamino-2-(2-fluorophenyl)-2-(2-hydroxyphenyl)butanolhemifumarate; and 4-Dimethylamino-2-(2-hydroxyphenyl)-2-(4-tolyl)butanolhemifumarate.

The following examples are shown for the purpose of illustrating thepresent invention.

EXAMPLE 1 2-(3-Phenyl-2,3-dihydrobenzofuran-3-yl)-N,N-dimethylethylamineoxalate

To a solution of 14.8 g (52 mmole)4-dimethylamino-2-(2-hydroxyphenyl)-2-phenylbutanol in 300 ml CH₂ Cl₂and 21.5 ml (156 mmole) triethylamine which had been cooled in an icebath for 20 minutes was added a solution of 6 ml (78 mmole)methanesulfonyl chloride in 50 ml CH₂ Cl₂. After the mixture was stirred3 hours at ice bath temperature, it was diluted with 800 ml CH₂ Cl₂,washed with 10% NaOH solution (2×125 ml) and saturated NaCl solution(125 ml), and dried over MgSO₄. Filtration and evaporation gave 14.0 gof a crude oil. A solution of 5 g of this material in 15 ml CH₂ Cl₂ wasadded to excess oxalic acid in Et₂ O. The precipitated solid wasrecrystallized from ethanol to give 4.2 g (63%) of crystals, m.p.158°-160°.

ANALYSIS: Calculated for C₁₈ H₂₁ NO.C₂ H₂ O₄ : 67.21%C; 6.49%H; 3.92%N.Found: 66.95%C; 6.49%H; 3.90%N.

EXAMPLE 22-(3-Phenyl-2,3-dihydrobenzofuran-3-yl)-N-cyano-N-methylethylamine

A solution of 10.9 g (103 mmole) cyanogen bromide and 23 g (86 mmole) of2-(3-phenyl-2,3-dihydrobenzofuran-3-yl)-N,N-dimethylethylamine in 500 mlCHCl₃ was refluxed for 4 hours. The solvent was evaporated and theresultant oil warmed to reflux in 500 ml water. After cooling, themixture was extracted with CH₂ Cl₂ (2×1 liter), and the organics werewashed with 1N HOAc (3×1 liter) and dried over K₂ CO₃. Evaporation gave20 g of an oil, which was chromatographed on 200 g silica gel using CH₂Cl₂ as an eluent to give 11 g of an oil which solidified on standing.Recrystallization from acetone/hexane gave 7.1 g (30%) of crystals, m.p.88°-92°.

ANALYSIS: Calculated for C₁₈ H₁₈ N₂ O: 77.67%C; 6.52%H; 10.07%N. Found:77.72%C; 6.47%H; 10.04%N.

EXAMPLE 32-(3-Phenyl-2,3-dihydrobenzofuran-3-yl)-N-(2,2,2-trichloroethoxycarbonyl)-N-methylethylamine

A mixture of 6.0 g (22.5 mole) of2-(3-phenyl-2,3-dihydrobenzofuran-3-yl)-N,N-dimethylethylamine, 3.72 ml(27 mmole) beta,beta,beta-trichloroethyl chloroformate, 12.4 g (90mmole) anhydrous K₂ CO₃, and 100 ml anhydrous CH₂ Cl₂ was stirred atroom temperature overnight. Water was then added to dissolve theinorganics and the layers were separated. The organics were washed withwater and dried over MgSO₄. Filtration and evaporation gave an oil,which was chromatographed with HPLC using 80% CH₂ Cl₂ /hexane as aneluent to give 6.4 g (66%) of an oil.

ANALYSIS: Calculated for C₂₀ H₂₀ Cl₃ NO₃ : 54.02%C; 4.70%H; 3.27%N.Found: 54.48%C; 4.73%H; 3.08%N.

EXAMPLE 4 2-(3-Phenyl-2,3-dihydrobenzofuran-3-yl)-N-methylethylaminehydrochloride

Activated zinc (14 g, 215 mmole) was added in several portions to asolution of 22 g (54.4 mmole) of2-(3-phenyl-2,3-dihydrobenzofuran-3-yl)-N-(2,2,2-trichloroethoxycarbonyl)-N-methylethylamine in 125 ml of glacial aceticacid under N₂ while cooling the mixture with a water bath. After 1 hourat room temperature, the reaction mixture was diluted with 600 ml CH₂Cl₂ and filtered through celite, and the solids were washed with CH₂Cl₂. The combined organics were evaporated to dryness and the resultantoil taken up in 800 ml CH₂ Cl₂. This was washed wit 50 ml saturated Na₂CO₃ and dried over MgSO₄. Filtration and evaporation gave 12.9 g of anoil. This oil was converted to its hydrochloride salt in Et₂ O and thesalt recrystallized from CH₃ CN to give 9.1 g (61%) of a solid, m.p.184°-187°.

ANALYSIS: Calculated for C₁₇ H₁₉ NO.HCl: 70.45%C; 6.96%H; 4.83%N. Found:70.58%C; 7.04H; 4.75%N.

EXAMPLE 52-(3-Phenyl-2,3-dihydrobenzofuran-3-yl)-N-cyclopropylmethyl-N-methylethylaminefumarate

A mixture of 4.0 g (15.8 mmole) of2-(3-phenyl-2,3-dihydrobenzofuran-3-yl)-N-methylethylamine, 1.54 g (17.1mmole) cyclopropylmethyl chloride, 6.9 g (50.0 mmole) K₂ CO₃ and 0.2 gKI in 40 ml DMF was warmed to 65° and maintained there for 4 hours.After cooling, the reaction mixture was poured into 400 ml water andextracted with Et₂ O (3×200 ml). The combined organics were washed withsaturated NaCl solution and dried over Na₂ SO₄. After filtration, thesolution was stirred with several grams of silica gel and decanted.After adding 1.85 g fumaric acid and stirring for 1 hour, 4.2 g of solidwas collected. This material was recrystallized from CH₃ CN to give 2.2g (33%) of crystals, m.p. 154°-156°.

ANALYSIS: Calculated for C₂₅ H₂₇ NO.C₄ H₄ O₄ : 73.55%C; 6.60%H; 2.96%N.Found: 73.39%C; 6.52%H; 2.98%N.

EXAMPLE 62-(3-Phenyl-2,3-dihydrobenzofuran-3-yl)-N-methyl-N-phenethylethylaminefumarate

A mixture of 4.0 g (15.8 mmole)2-(3-phenyl-2,3-dihydrobenzofuran-3-yl)-N-methylethylamine, 6.9 g (50.0mmole) anhydrous K₂ CO₃, 2.35 ml (17.1 mmole) phenethyl bromide, 0.2 gpotassium iodide and 40 ml DMF was warmed to 80° and maintained therefor 2 hours. After cooling, the mixture was poured into 400 ml water andextracted with Et₂ O (3×250 ml). The combined organics were washed withsaturated NaCl solution and dried over MgSO₄. The crude product,obtained by filtration and evaporation, was converted to a fumarate saltin Et₂ O. This was recrystallized from CH₃ CN to give 2.5 g (33%) ofsolid, m.p. 135.5°-138°.

ANALYSIS: Calculated for C₂₅ H₂₇ NO.C₄ N₄ O₄ : 73.55%C; 6.60%H; 2.96%N.Found: 73.39%C; 6.52%H; 2.98%N.

EXAMPLE 72-(3-Phenyl-2,3-dihydrobenzofuran-3-yl)-N-(2-cyanoethyl)-N-methylethylamineoxalate

Acrylonitrile (1.18 ml, 18 mmole) was added dropwise to 4.0 g (15.8mmole) of 2-(3-phenyl-2,3-dihydrobenzofuran-3-yl)-N-methylethylamine.The resultant mixture was stirred at room temperature for 1.5 hours andat 75° for 3 hours under N₂. The cooled mixture was diluted with 400 mlEt₂ O and filtered. The filtrate was treated with oxalic acid/Et₂ O andthe resultant salt was recrystallized from ethanol to give 3.2 g (50%)of a solid, m.p. dec. greater than 144°.

ANALYSIS: Calculated for C₂₀ H₂₂ N₂ O.C₂ H₂ O₄ : 66.65%C; 6.10%H;7.07%N. Found: 66.26%C; 6.06%H; 6.97%N.

EXAMPLE 83-(3-Phenyl-2,3-dihydrobenzofuran-3-yl)-N,N-dimethylpropylamine oxalate

To a solution of 5-dimethylamino-2-(2-hydroxyphenyl)-2-phenylpentanol(15.0 g, 50 mmol) in CH₂ Cl₂ (300 ml) and Et₃ N (21.5 ml, 156 mmol)maintained at 5° was added a solution of methanesulfonyl chloride (6.0ml, 78 mmol) in CH₂ Cl₂ (50 ml). After the addition was completed, thereaction mixture was diluted with CH₂ Cl₂ (200 ml), washed with 5% NaOHsolution (1×250 ml) and saturated NaCl solution (1×250 ml), and driedover Na₂ SO₄. Filtration and evaporation gave 12.4 g of a crude oil. Asolution of this crude amine in CH₂ Cl₂ (50 ml) was added to a stirredsolution of anhydrous oxalic acid (6.0 g, 66 mmol) in anhydrous Et₂ O(500 ml). The precipitated solid was filtered and recrystallized fromethanol (150 ml) to afford 4.5 g (25 %) of platelets, m.p.140.0°-141.0°.

ANALYSIS: Calculated for C₁₉ H₂₃ NO.C₂ H₂ O₄ : 67.91%C; 6.78%H; 3.77%N.Found: 67.74%C; 6.77%H; 3.71%N.

EXAMPLE 93-(3-Phenyl-2,3-dihydrobenzofuran-3-yl)-N-(2,2,2-trichloroethoxycarbonyl)-N-methylpropylamine

A mixture of3-(3-phenyl-2,3-dihydrobenzofuran-3-yl)-N,N-dimethylpropylamine (7.40 g,26 mmol), anhydrous K₂ CO₃ (14.3 g, 104 mmol), and CH₂ Cl₂ (125 ml) wasstirred at 5°. A solution of 2,2,2-trichloroethyl chloroformate (4.3 ml,32 mmol) in CH₂ Cl₂ (5 ml) was added dropwise over 15 minutes. Thereaction mixture was stirred at room temperature for 4 hours. Water wasthen added to dissolve the inorganic salts and the phases wereseparated. The organic phase was washed with saturated NaHCO₃ andsaturated NaCl, dried over Na₂ SO₄, filtered, and evaporated in vacuo togive 7.6 g of a crude oil. This residue was chromatographed by HPLCusing CH₂ Cl₂ /hexane (2:1, by volume) as an eluent to yield 3.5 g (30%)of an oil.

ANALYSIS: Calculated for C₂₁ H₂₂ Cl₃ NO₃ : 56.96%C; 5.01%H; 3.16%N.Found: 56.72%C; 4.96%H; 3.07%N.

EXAMPLE 10 3-(3-Phenyl-2,3-dihydrobenzofuran-3-yl)-N-methylpropylaminehydrochloride

Activated zinc (33.5 g, 516 mmol) was added in several portions to asolution of3-(3-phenyl-2,3-dihydrobenzofuran-3-yl)-N-(2,2,2-trichloroethoxycarbonyl)-N-methylpropylamine(57 g, 129 mmol) in glacial HOAc (300 ml) while cooling the mixture witha water bath. After stirring 3 hours at room temperature, the reactionmixture was diluted with CH₂ Cl₂ (500 ml), filtered, and the solidswashed with CH₂ Cl₂ (200 ml). The combined organics were concentrated invacuo and the residue (63 g) was dissolved in CH₂ Cl₂ (500 ml). Thissolution was washed with 5% NaOH (1×400 ml) and saturated NaHCO₃ (2×500ml), dried over Na₂ SO₄, filtered, and evaporated to afford 26 g (74%)of a crude amine. The amine (3.0 g) was converted to its hydrochloridesalt in Et₂ O and recrystallized from CH₃ CN to yield 2.4 g (52%) of asolid, m.p. 180.0°-181.5°.

ANALYSIS: Calculated for C₁₈ N₂₁ NO.HCl: 71.16%C; 7.30%H; 4.61%N. Found:71.45%C; 7.34%H; 4.50%N.

EXAMPLE 113-(3-Phenyl-2,3-dihydrobenzofuran-3-yl)-N-methyl-N-phenethylpropylamineoxalate

A mixture of 3-(3-phenyl-2,3-dihydrobenzofuran-3-yl)-N-methylpropylamine(6.0 g, 22.4 mmol), anhydrous K₂ CO₃ (6.9 g, 50 mmol), KI (0.3 g), andphenethyl bromide (3.3 ml, 24 mmol) in DMF (100 ml) was warmed to 80°and maintained there for 4 hours. After cooling, the reaction mixturewas poured into ice-water (500 ml) and extracted with Et₂ O (3×250 ml).The combined organics were washed with saturated aqueous NaCl, driedover Na₂ SO₄, and evaporated to afford 7.7 g of a crude amine. The crudeproduct (3.0 g) was chromatographed on SiO₂ (0-2% MeOH/CH₂ Cl₂) to give2.2 g of pure amine. A solution of the amine in CH₂ Cl₂ (15 ml) wasadded to a stirred solution of anhydrous oxalic acid (0.8 g, 8.8 mol) inanhydrous Et₂ O (350 ml). The precipitated salt was filtered andrecrystallized from boiling EtOAc (150 ml), washed with Et₂ O to yield2.1 g (52%) of salt, m.p. 124°-126°.

ANALYSIS: Calculated for C₂₆ H₂₉ NO.C₂ H₂ O₄ : 72.86%C; 6.77%H; 3.03%N.Found: 73.01%C; 6.72%H; 3.05%N.

EXAMPLE 123-(3-Phenyl-2,3-dihydrobenzofuran-3-yl)-N-cyclopropylmethyl-N-methylpropylamineoxalate

Cyclopropanecarboxylic acid chloride (3.15 g, 30 mmol) was addeddropwise to a solution of3-(3-phenyl-2,3-dihydrobenzofuran-3-yl)-N-methylpropylamine (6.6 g, 25mmol) and pyridine (2.8 g, 35 mmol) in CH₂ Cl₂ (100 ml) at roomtemperature and the mixture was stirred overnight. The reaction mixturewas washed with 5% HCl (2×100 ml), stirred with 5% NaOH (150 ml) for 1hour, washed with saturated NaCl, dried over Na₂ SO₄, filtered, andconcentrated in vacuo to give 8.2 g of an oily amide (99% by GC).

A solution of the amide (8.2 g, 24 mmol) in THF (30 ml) was addeddropwise to a stirred suspension of LiAlH₄ (0.93 g, 24 mmol) in THF (85ml) at room temperature. The reaction mixture was stirred 1 hour,quenched with saturated NH₄ Cl (100 ml), and the phases were separated.The organic phase was evaporated in vacuo and the crude amine dissolvedin EtOAc (150 ml), washed with 10% Na₂ CO₃ (2×75 ml) and saturated NaCl(1×75 ml), dried over Na₂ SO₄, filtered and concentrated in vacuo togive 7.0 g of the amine. A solution of the amine in Et₂ O (50 ml) wasadded dropwise to a stirred solution of anhydrous oxalic acid (2.1 g, 23mmol) in Et₂ O (900 ml). The precipitated salt was filtered andrecrystallized from a boiling EtOAc/MeOH (300:40 ml) solution to yield5.7 g (55%) of a solid, m.p. 147°-148°.

ANALYSIS: Calculated for C₂₂ H₂₇ NO.C₂ H₂ O₄ : 70.05%C; 7.10%H; 3.40%N.Found: 69.98%C; 7.05%H; 3.35%N.

EXAMPLE 133-(3-Phenyl-5-chloro-2,3-dihydrobenzofuran-3-yl)-N,N-dimethylpropylamineoxalate

To a solution of5-dimethylamino-2-(5-chloro-2-hydroxyphenyl)-2-phenylpentanol (22.5 g,68 mmol) in CH₂ Cl₂ (400 ml) and Et₃ N (18.8 ml, 136 mmol) maintained at5° was added methanesulfonyl chloride (7.8 ml, 102 mmol). The reactionmixture was stirred 2 hours, washed with 5% NaOH (1×250 ml), water andsaturated NaCl, and dried over Na₂ SO₄. Filtration and evaporation gave20.5 g of a crude residue which was chromatographed by HPLC (2% MeOH:CH₂Cl₂) to yield 4.8 g of the amine. A solution of the amine (4.8 g) in CH₂Cl₂ (50 ml) was added to a stirred solution of anhydrous oxalic acid(1.6 g, 18 mmol) in Et₂ O (300 ml). The precipitated sald (4.8 g) wasfiltered and recrystallized from MeCN (100 ml) to yield 3.9 g (14%) ofcrystals, m.p. 163°-164°.

ANALYSIS: Calculated for C₁₉ H₂₂ ClNO.C₂ H₂ O₄ : 62.14%C; 5.97%H;3.45%N. Found: 62.46%C; 5.94%H; 3.33%N.

EXAMPLE 143-[3-(4-Tolyl)-2,3-dihydrobenzofuran-3-yl]-N,N-dimethylethylaminefumarate

To a solution of 4-dimethylamino-2-(2-hydroxyphenyl)-2-(4-tolyl)butanol(18 g, 60 mmol) in CH₂ Cl₂ (400 ml) and Et₃ N (14.5 ml, 105 mmol)maintained at 0° was added methanesulfonyl chloride (6.9 ml, 90 mmol).The reaction mixture was stirred 2 hours, and then stirred with 5% NaOH(100 ml) for 3 hours. The organic layer was separated, washed with waterand saturated NaCl, and dried over Na₂ SO₄. Filtration and evaporationgave 11.3 g of a crude residue, which was chromatographed by HPLC (3.5%MeOH/CH₂ Cl₂) to yield 4.9 g of an amine. A solution of the amine (4.9g, 17.5 mmol) in CH₂ Cl₂ (50 ml) was added to a stirred solution offumaric acid (3.3 g, 28 mmol) in 15% ethanol/ether (350 ml). Theprecipitated salt (7.7 g) was filtered and recrystallized from MeCN (140ml) to yield 6.8 g (29%) of flakes, m.p. 138°-140°.

ANALYSIS: Calculated for C₁₉ H₂₃ NO.C₄ H₄ O₄ : 69.49%C; 6.86%H; 3.52%N.Found: 69.92%C; 6.95%H; 3.62%N. A solution of the amine (4.8 g, 15 mmol)in CH₂ Cl₂ (50 ml) was added to a stirred solution of anhydrous oxalicacid (1.6 g, 18 mmol) in Et₂ O (300 ml). The precipitated salt (4.8 g)was filtered and recrystallized from MeCN (100 ml) to yield 3.9 g (14%)of crystals, m.p. 163°-164°.

ANALYSIS: Calculated for C₁₉ H₂₂ ClNO.C₂ H₂ O₄ : 62.14%C; 5.97%H;3.45%N. Found: 62.46%C; 5.94%H; 3.33%N.

EXAMPLE 143-[3-(4-Tolyl)-2,3-dihydrobenzofuran-3-yl]-N,N-dimethylethylaminefumarate

To a solution of 4-dimethylamino-2-(2-hydroxyphenyl)-2-(4-tolyl)butanol(18 g, 60 mmol) in CH₂ Cl₂ (400 ml) and Et₃ N (14.5 ml, 105 mmol)maintained at 0° was added methanesulfonyl chloride (6.9 ml, 90 mmol).The reaction mixture was stirred 2 hours, and then stirred with 5% NaOH(100 ml) for 3 hours. The organic layer was separated, washed with waterand saturated NaCl, and dried over Na₂ SO₄. Filtration and evaporationgave 11.3 g of a crude residue, which was chromatographed by HPLC (3.5%MeOH/CH₂ Cl₂) to yield 4.9 g of an amine. A solution of the amine (4.9g, 17.5 mmol) in CH₂ Cl₂ (50 ml) was added to a stirred solution offumaric acid (3.3 g, 28 mmol) in 15% ethanol/ether (350 ml). Theprecipitated salt (7.7 g) was filtered and recrystallized from MeCN (140ml) to yield 6.8 mg (29%) of flakes, m.p. 138°-140°.

ANALYSIS: Calculated for C₁₉ H₂₃ NO.C₄ H₄ O₄ : 69.49%C; 6.86%H; 3.52%N.Found: 69.92%C; 6.95%H; 3.62%N.

EXAMPLE 153-[3-(2-Fluorophenyl)-2,3-dihydrobenzofuran-3-yl]-N,N-dimethylethylaminehydrochloride

To a solution of 4-dimethylamino-2-(2-hydroxyphenyl)-2-(2-tolyl)-butanol(36 g, 120 mmol) in CH₂ Cl₂ (500 ml) and Et₃ N (25 ml, 180 mmol)maintained at 0° was added methanesulfonyl chloride (11.6 ml, 150 mmol).The reaction mixture was warmed to room temperature and stirredovernight. The mixture was washed with H₂ O (2×300 ml), 10% Na₂ CO₃(2×200 ml) and saturated NaCl, dried over Na₂ SO₄, and stirred withsilica gel (10 g). Filtration and evaporation gave 17.5 g (52%) of theamine. A solution of the amine (16.5 g, 59 mmol) in CH₂ Cl₂ (100 ml) wasadded to a stirred solution of fumaric acid (8.0 g, 69 mmol) in 10%ethanol/ether (1100 ml). The precipitated salt (20 g) was filtered anddried. The crude fumarate (3.9 g) was recrystallized from MeCN (450 ml)to yield 3.1 g (35%) of flakes, m.p. 188°-190°.

ANALYSIS: Calculated for C₁₉ H₂₃ NO.C₄ H₄ O₄ : 69.49%C; 6.86%H; 3.52%N.Found: 69.56%C; 6.82%H; 3.71%N.

EXAMPLE 163-[3-(2-Fluorophenyl)-2,3-dihydrobenzofuran-3-yl]-N,N-dimethylethylaminehydrochloride

To a solution of4-dimethylamino-2-(2-hydroxyphenyl)-2-(2-fluorophenyl)butanol (10.7 g,35 mmol) in CH₂ Cl₂ (200 ml) and Et₃ N (7.3 ml, 53 mmol) maintained at0° was added methanesulfonyl chloride (3.4 ml, 44 mmol). The reactionmixture was warmed to room temperature and stirred overnight. Themixture was washed with H₂ O (2×300 ml), 10% Na₂ CO₃ (2×200 ml) andsaturated NaCl, dried over Na₂ SO₄, and stirred with silica gel (3 g).Filtration and evaporation gave 6.2 g (62%) of the amine. The crudeamine (6.2 g) was chromatographed on silica gel eluting with CH₂ Cl₂ togive 3.2 g of an oil. A solution of the amine (3.2 g, 11.2 mmol) in CH₂Cl₂ (15 ml) was added dropwise to an ethereal HCl solution (300 ml). Theprecipitated salt was recrystallized from MeCN (30 ml) to yield 2.2 g(20%) of crystals, m.p. 211°-213°.

ANALYSIS: Calculated for C₁₈ H₂₀ FNO.HCl: 67.17%C; 6.59%H; 4.35%N.Found: 67.13%C; 6.48%H; 4.24%N.

EXAMPLE 17 alpha-(2-Methoxyphenyl)phenylacetonitrile

To a solution of 30 g (0.125 mole)alpha-(2-methoxyphenyl)-phenylacetaldoxime in 300 ml CH₂ Cl₂ was added22 ml (0.15 mole) trifluoroacetic anhydride in 100 ml CH₂ Cl₂ at 10°over 30 minutes. After stirring at room temperature for 1 hour, themixture was refluxed for 2 hours. After cooling to room temperature,this was shaken successively with 200 ml 0.2N NaOH, 150 ml saturated Na₂CO₃, and 150 ml saturated NaCl solution, and dried over MgSO₄.Filtration and evaporation gave 33 g of an oil, which was short-pathdistilled to give 16 g (56%) of a thick oil which solidified onstanding, m.p. 81°-84°. An analytical sample was prepared by onerecrystallization from cyclohexane giving needles, m.p. 83°-85°.

ANALYSIS: Calculated for C₁₅ H₁₃ NO: 80.69%C; 5.88%H; 6.27%N. Found:80.66%C; 5.98%H; 6.25%N.

EXAMPLE 18 4-Dimethylamino-2-(2-methoxyphenyl)-2-phenylbutyronitrileoxalate

To a solution of 6.4 ml (46 mmole) diisopropylamine in 50 ml dry THFmaintained at -70° under nitrogen was added 18.2 ml (44 mmole)n-BuLi/hexane (2.42M). The mixture was stirred at -70° for 15 minutesand brought to -30°. A solution of 9.16 g (40 mmole)alpha-(2-methoxyphenyl)-phenylacetonitrile in 50 ml THF was addeddropwise and the resultant solution placed in an ice bath for 15 minutesand further stirred at room temperture for 30 minutes. After cooling themixture to 0°, 11 ml (92 mmole) freshly distilled dimethylaminoethylchloride was added. The mixture was stirred at room temperature for 15minutes, then warmed to reflux and maintained there for 1.5 hours. Thereaction was quenched with 5 ml water and the volatiles evaporated invacuo. The residue was taken up in 1 liter CH₂ Cl₂, washed with water(2×200 ml), and dried over MgSO₄. Filtration and evaporation gave anoil, which was taken up in a minimum amount of CHCl₃ and then added to asolution of oxalic acid in Et₂ O. The precipitated salt was collected ona filter, yielding 10.8 g (68%) of a solid, m.p. 175°-178°. Ananalytical sample was prepared by recrystallization from EtOH, m.p.177°-179°.

ANALYSIS: Calculated for C₁₉ H₂₂ N₂ O.C₂ H₂ O₄ : 65.61%C; 6.29%H;7.29%N. Found: 65.37%C; 6.33%H; 7.24%N.

EXAMPLE 19 5-Dimethylamino-2-(2-methoxyphenyl)-2-phenylvaleronitrilehydrochloride

To a solution of diisopropylamine (6.4 ml, 46 mmol) in anhydrous THF (50ml) maintained at -70° under nitrogen was added n-BuLi/hexane (2.2M, 20ml, 44 mmol). The solution was stirred at -70° for 15 minutes andbrought to -30° C. A solution ofalpha-(2-methoxyphenyl)-phenylacetonitrile (9.16 g, 40 mmol) in THF (50ml) was added dropwise and the resultant solution was allowed to warm to20° and stirred for 0.5 hour. Distilled 3-dimethylaminopropyl chloride(11.2 g, 92 mmol) was added dropwise and the mixture was refluxed 16hours. The reaction mixture was cooled and quenched with H₂ O (5 ml),the volatiles were evaporated in vacuo and the residue was dissolved indichloromethane (300 ml) and washed with H₂ O (3×100 ml) until the pH ofthe aqueous phase became 8. The organic solution was dried over Na₂ SO₄,filtered, and evaporated in vacuo. The residue was dissolved in diethylether (300 ml) and saturated with gaseous HCl. The crude precipitatedsalt (10.4 g, 84%) was collected and dried. Analytically pure material(5.2 g, 38%) was obtained by recrystallization from acetonitrile, m.p.194.0°-195.5°.

Analysis: Calculated for C₂₀ H₂₄ N₂ O.HCl: 69.65%C; 7.34%H; 8.12%N.Found: 69.59%C; 7.29%H; 8.25%N.

EXAMPLE 20 5-Chloro-2-methoxy-alpha-phenylbenzeneacetonitrile

To a solution of o-anisaldehyde (136 g, 1.0 mole) in DMF (1000 ml) wasadded N-chlorosuccinimide (147 g, 1.10 mole). The reaction mixture wasstirred 20 hours at 60°, cooled, poured into ice-water, and extractedwith Et₂ O. The solvent was removed in vacuo to yield 172 g of crystals.Recrystallization from cyclohexane (800 ml) gave 137 g (80%) of5-chloro-2-methoxybenzaldehyde, m.p. 77°-79°.

A Grignard reagent was prepared by reacting bromobenzene (126 g, 0.8mole) with Mg (22 g, 0.9 mole) in anhydrous Et₂ O (500 ml). A solutionof said aldehyde (68 g, 0.4 mole) in Et₂ O (700 ml) was added to the C₆H₅ MgBr solution at a rate fast enough to maintain reflux. The reactionmixture was quenched with saturated NH₄ Cl. The organic layer wasseparated, washed with water and saturated NaHCO₃, dried (Na₂ SO₄) andreduced in vacuo to yield 99 g (99%) of5-chloro-2-methoxy-alphaphenyl-benzylalcohol which solidified uponstanding.

To a solution of said alcohol (99 g, 0.4 mole) and pyridine (40 g, 0.5mole) in CHCl₃ (1000 ml) was added SOCl₂ (52 g, 0.44 mol) fast enough tomaintain reflux. The reaction mixture was cooled and quenched withwater. The organic phase was washed with 5% HCl and saturated NaHCO₃,dried over Na₂ SO₄, and reduced in vacuo to yield 109 g of a crude oil,which deposited crystals upon standing. Decantation of the oil left 75 g(69%) of crystalline alpha,5-dichloro-2-methoxy-alpha-phenyltoluene.

To a solution of the above product (15 g, 56 mmol) in dry MeCN (250 ml)was added AgCN (10 g, 75 mmol). The reaction mixture was refluxed 8hours, filtered, and reduced in vacuo to afford 16 g of an oil which waschromatographed by HPLC using CH₂ Cl₂ /hexane (1:2 by volume) as aneluent, to yield 6 g of5-chloro-2-methoxy-alpha-phenylbenzeneacetonitrile (90% pure by GC)contaminated with the corresponding isonitrile.

A solution of the chromatographed nitrile in benzene (25 ml) was stirredwith 50% H₂ SO₄ (80 ml) at room temperature for 16 hours. The organicphase was separated, stirred with Na₂ CO₃, filtered, and reduced invacuo to give 5 g of the nitrile which was again chromatographed on 80 gSiO₂ (CH₂ Cl₂ /hexane, 1:1 by volume) to give an oil (3.5 g) whichsolidified upon standing. The solid nitrile was recrystallized fromhexane (150 ml) to yield 2.7 g (18%) of powder, m.p. 80.0°-81.0°. Ayield of 46% was obtained on a larger scale nitrile synthesis.

ANALYSIS: Calculated for C₁₅ H₁₂ ClNO: 69.90%C; 4.70%H; 5.44%N. Found:70.02%C; 4.81%H; 5.29%N.

EXAMPLE 215-Dimethylamino-2-(5-chloro-2-methoxyphenyl)-2-phenylvaleronitrileoxalate

To a solution of diisopropylamine (9.4 ml, 67 mmol) at -70° was addedn-BuLi/hexane (2.2M, 29 ml, 64 mmol), and this solution was stirred andwarmed to -30°. A solution of 5-chloro-2-methoxy-alpha-phenylbenzeneacetonitrile (15.0 g, 58 mmol) in THF (60 ml) was added dropwise and theresultant mixture was warmed to 5°. Distilled 3-dimethylaminopropylchloride (14 g, 115 mmol) was added and the mixture refluxed 20 hours.The reaction mixture was cooled and quenched with H₂ O (5 ml) and thevolatiles were evaporated in vacuo. The resultant residue was dissolvedin CH₂ Cl₂ (350 ml), washed with H₂ O (200 ml) and saturated NaCl, driedover Na₂ SO₄, filtered, and reduced in vacuo. This residue (21 g) waschromatographed by HPLC (5% MeOH:CH₂ Cl₂) to yield 16 g of the amine. Asolution of the amine (3.6 g, 10.5 mmol) in Et₂ O (50 ml) was added to astirred solution of anhydrous oxalic acid (1.1 g, 12 mmol) in anhydrousEt₂ O (300 ml). The precipitated salt was filtered (3.4 g) andrecrystallized from boiling MeCN (80 ml) to yield 2.8 g (40%) of salt,m.p. 183.0°-183.5°.

ANALYSIS: Calculated for C₂₀ H₂₃ ClN₂ O.C₂ H₂ O₄ : 61.03%C 5.83%H6.47%N. Found: 60.89%C 5.59%H 6.41%N.

EXAMPLE 22 alpha-(2-Methoxyphenyl)-4-tolylacetonitrile

A solution of o-anisaldehyde (43 g, 320 mmol) in Et₂ O (200 ml) wasadded dropwise to 4-tolylmagnesium bromide/Et₂ O (2M, 380 ml, 760 mmol).The reaction mixture was quenched with 5% HCl (1000 ml) and the organiclayer was separated, washed with water and saturated NaHCO₃, dried overNa₂ SO₄ and reduced in vacuo to yield 84 g of the alcohol.

To a solution of the crude alcohol (84 g) in CH₂ Cl₂ (400 ml) was addedSOCl₂ (42 g, 350 mmol). The reaction mixture was refluxed 2 hours, thencooled and the volatiles evaporated in vacuo to yield 79 g of the crudechloride.

To a solution of the chloride (79 g, 320 mmol) in dry MeCN (500 ml) wasadded AgCN (43 g, 320 mmol). The reaction mixture was refluxed 26 hours,filtered, and reduced in vacuo to afford 79 g of an oil which waschromatographed by HPLC using CH₂ Cl₂ /hexane (1:2 by volume) as aneluent to yield 47 g (62%) of an oil.

ANALYSIS: Calculated for C₁₆ H₁₅ NO: 80.97%C; 6.38%H; 5.90%N. Found:81.27%C; 6.43%H; 5.59%N.

EXAMPLE 23 alpha-(2-Methoxyphenyl)-2-tolylacetonitrile

To a solution of o-bromotoluene (300 g, 1.75 mole) in THF (1500 ml) at-60° under N₂ was added n-BuLi/hexane (2.5M, 375 ml, 0.94 mole) and thissolution was stirred 2 hours. A solution of o-anisaldehyde (119 g, 0.88mole) in THF (400 ml) was added dropwise over 1 hour. The reactionmixture was left standing at room temperature overnight and thereafterquenched with H₂ O (20 ml), and the volatiles were evaporated in vacuo.The residue was dissolved in CH₂ Cl₂ (1000 ml), washed with dilute HOAc,H₂ O and dilute NaHCO₃, dried over Na₂ SO₄, filtered, and reduced invacuo to give 215 g of the crude alcohol.

To a solution of the alcohol (215 g) in CH₂ Cl₂ (1000 ml) was addedSOCl₂ (115 g, 0.97 mole). The reaction mixture was refluxed 2 hours,then cooled and the volatiles evaporated in vacuo to yield 226 g of thecrude chloride.

To a solution of the chloride (226 g) in dry MeCN (1500 ml) was addedAgCN (118 g, 0.88 mole). The reaction mixture was refluxed 24 hours,filtered, and reduced in vacuo to afford 227 g of an oil. The nitrilewas chromatographed by HPLC (hexane/CH₂ Cl₂, 2:1 by volume) to yield 111g (53%) of a solid. The nitrile (5.4 g) was then recrystallized fromhexane (110 ml) to yield 4.5 g (44%) of crystals, m.p. 95.0°-95.5°.

ANALYSIS: Calculated for C₁₆ H₁₅ NO: 80.97%C; 6.38%H; 5.90%N. Found:80.99%C; 6.56%H; 5.85%N.

EXAMPLE 24 4-Dimethylamino-2-(2-methoxyphenyl)-2-(4-tolyl)butyronitrilemaleate

To a solution of diisopropylamine (28 ml, 200 mmol) in anhydrous THF(1000 ml) at -70° was added n-BuLi/hexane (2.4M, 79 ml, 190 mmol) andthis solution was stirred and warmed to -30°. A solution ofalpha-(2-methoxyphenyl)-4-tolylacetonitrile (41 g, 173 mmol) in THF (200ml) was added and the resultant mixture was warmed to 5°. Distilleddimethylaminoethyl chloride (37 g, 346 mmol) was added and the mixturerefluxed 24 hours. The reaction mixture was cooled, quenched with H₂ O(50 ml), and the volatiles evaporated in vacuo. The residue wasdissolved in CH₂ Cl₂ (750 ml), washed with H₂ O and saturated NaCl,dried over Na₂ SO₄, filtered, and reduced in vacuo to afford 64 g of acrude residue. A 20 g portion of the crude residue was chromatographedby HPLC (2.5% MeOH:CH₂ Cl₂) to yield 10.8 g of the amine. A solution ofthe amine (10.8 g, 35 mmol) in CH₂ Cl₂ (50 ml) was added to a stirredsolution of maleic acid (4.5 g, 39 mmol) in Et₂ O (300 ml). Theprecipitated salt (14.8 g) was recrystallized from EtOH (170 ml) toyield 12.5 g (55%) of crystals, m.p. 175°-176.5°.

ANALYSIS: Calculated for C₂₀ H₂₄ N₂ O.C₄ H₄ O₄ : 67.90%C; 6.66%H;6.60%N. Found: 67.63%C; 6.68%H; 6.65%N.

EXAMPLE 25 4-Dimethylamino-2-(2-methoxyphenyl)-2-(2-tolyl)butyronitrilemaleate

To a solution of diisopropylamine (74 ml, 530 mmol) in anhydrous THF(2000 ml) at -70° was added n-BuLi/hexane (2.4M, 210 ml, 506 mmol) andthis solution was stirred and warmed to -30°. A solution ofalpha-(2-methoxyphenyl)-2-tolylacetonitrile (109 g, 460 mmol) in THF(400 ml) was added and the resultant mixture was warmed to 5°. Distilleddimethylaminoethyl chloride (93 g, 860 mmol) was added and the mixturerefluxed 24 hours. The reaction mixture was cooled, quenched with water(50 ml), and the volatiles evaporated in vacuo. The residue wasdissolved in CH₂ Cl₂ (1000 ml), washed with water and saturated NaCl,dried over Na₂ SO₄, filtered and reduced in vacuo. A 15 g portion of thecrude residue (143 g) was chromatographed by HPLC (3% MeOH/CH₂ Cl₂) toyield 10.8 g of the amine. A solution of the amine (10.8 g, 35 mmol) inEt₂ O/CH₂ Cl₂ (50 ml, 1:1) was added to a stirred solution of maleicacid (5.8 g, 50 mmol) in Et₂ O (500 ml). The precipitated salt (15 g)was recrystallized from EtOH (100 ml) to yield 13.4 g (66%) of crystals,m.p. 166°-167.5°.

ANALYSIS: Calculated for C₂₄ H₂₈ N₂ O₅ : 67.90%C; 6.66%H; 6.60;l %N.Found: 67.92%C; 6.47%H; 6.43%N.

EXAMPLE 26 alpha-(2-Methoxyphenyl)-2-fluorophenylacetonitrile

To a solution of 2-bromofluorobenzene (371 g, 2.12 mole) in THF (2000ml) at -60° under N₂ was added n-BuLi/hexane (2.4M, 860 ml, 2.1 mole)and this solution stirred 0.5 hour. A solution of o-anisaldehyde (144 g,1.06 mole) in THF (400 ml) was added dropwise over 1 hour. The reactionmixture was stirred at -60° for 4 hours, then quenched with H₂ O (50ml), warmed to room temperature and the volatiles evaporated in vacuo.The residue was dissolved in EtOAc (1000 ml), washed with 5% HCl and H₂O, dried over Na₂ CO₃, filtered, and reduced in vacuo to give 264 g ofthe crude alcohol.

To a solution of the alcohol (264 g) in CH₂ Cl₂ (1500 ml) was addedSOCl₂ (139 g, 1.17 mole). The reaction mixture was refluxed 3 hours,then cooled and the volatiles evaporated in vacuo to yield 284 g of thecrude chloride.

To a solution of the chloride (284 g) in dry MeCN (2000 ml) was addedAgCN (1.06 mol, 142 g). The reaction mixture was refluxed 24 hours,filtered, and reduced in vacuo to afford 298 g of an oil. The nitrilewas chromatographed by HPLC (hexane/CH₂ Cl₂, 2:1) to yield 120 g (47%)of a solid contaminated with the isonitrile. This was dissolved in CH₂Cl₂ (600 ml) and stirred with concentrated HCl (150 ml) overnight atroom temperature. The organic phase was separated, stirred with Na₂ CO₃,filtered, and reduced in vacuo to give 80 g of the nitrile. This wasagain chromatographed by HPLC (hexane/CH₂ Cl₂, 2:1) to yield 59 g (23%)of a solid. The nitrile (7 g) was recrystallized from C₆ H₁₂ (70 ml) toyield 4.1 g (14%) of crystals, m.p. 97°-98°.

ANALYSIS: Calculated for C₁₅ H₁₂ FNO: 74.67%C; 5.02%H; 5.80%N. Found:74.85%C; 5.09%H; 5.71%N.

EXAMPLE 274-Dimethylamino-2-(2-fluorophenyl)-2-(2-methoxyphenyl)butyronitrilefumarate

To a solution of diisopropylamine (44.5 ml, 317 mmol) in THF (1000 ml)at -70° was added n-BuLi/hexane (1.3M, 234 ml, 304 mmol) and thissolution was stirred and warmed to -30°. A solution ofalpha-(2-fluorophenyl)-2-methoxyphenylacetonitrile (67 g, 276 mmol) inTHF (200 ml) was added and the reaction mixture was warmed to 5°.Distilled dimethylaminoethyl chloride (50 g, 460 mmol) was added and themixture refluxed 24 hours. The reaction mixture was cooled, quenchedwith water (50 ml), and the volatiles evaporated in vacuo. The residuewas dissolved in CH₂ Cl₂ (1000 ml), washed with water and saturatedNaCl, dried over Na₂ SO₄, filtered, and reduced in vacuo. The cruderesidue (80 g) was chromatographed by HPLC (3% MeOH/CH₂ Cl₂) to yield 70g (81%) of the amine. A solution of the amine (3.1 g, 10 mmol) in CH₂Cl₂ (15 ml) was added to a stirred solution of fumaric acid (1.5 g, 13mmol) in 5% EtOH/Et₂ O solution (500 ml). The precipitated salt (2.6 g)was recrystallized from EtOAc (125 ml) to yield 2.2 g (42%) of crystals,m.p. 146°-148°.

ANALYSIS: Calculated for C₁₉ H₂₁ FN₂ O.C₄ H₄ O₄ : 64.47%C; 5.89%H;6.53%N. Found: 64.65%C; 5.77%H; 6.69%N.

EXAMPLE 28 4-Dimethylamino-2-(2-hydroxyphenyl)-2-phenylbutanolhydrochloride

A solution of 28.6 g (102 mmole)2-(2-oxo-3-phenyl-3-dihydrobenzofuranyl)-N,N-dimethylethylamine in 300ml anhydrous Et₂ O was added to 7.74 g (204 mmole) LiAlH₄ in 150 ml Et₂O at ice bath temperature and this mixture stirred at that temperaturefor 30 minutes. After further stirring for 2 hours at room temperature,the reaction mixture was quenched with saturated Na₂ SO₄, filtered, andthe solids washed with excess EtOAc (4×350 ml). The combined organicswere washed with saturated Na₂ CO₃ (300 ml) and saturated NaCl (200 ml),and dried over Na₂ SO₄. Filtration and evaporation gave 28 g of a crudeoil which solidified on standing. A solution of 5 g of this material ina minimum amount of CH₂ Cl₂ was added to excess Et₂ O/HCl. Filtration ofthe precipitated salt gave 5.5 g of a solid which was recrystallizedfrom EtOH to give 3.2 g (57%) of crystals, m.p. 199°-201°.

ANALYSIS: Calculated for C₁₈ H₂₃ NO₂.HCl: 67.17%C; 7.52%H. Found:67.08%C; 7.52%H.

EXAMPLE 29 5-Dimethylamino-2-(2-hydroxyphenyl)-2-phenylpentanol oxalate

A solution of3-(2-oxo-3-phenyl-3-dihydrobenzofuranyl)-N,N-dimethylpropylamine (103 g,349 mmol) in anhydrous THF (400 ml) was added to a suspension of LiAlH₄(15.3 g, 384 mmol) in Et₂ O (300 ml) at ice bath temperature and thismixture stirred for 2 hours. After further stirring 1 hour at roomtemperature the reaction mixture was quenched with saturated Na₂ SO₄,filtered and the solids washed with EtOAc (4×500 ml). The combinedorganic phases were washed with saturated Na₂ CO₃ (500 ml) and saturatedNaCl (500 ml), and dried over Na₂ SO₄. Filtration and evaporation gave66 g of a crude oil which solidified on standing. A solution of 40 g ofthis material in CH₂ Cl₂ (60 ml) was added to a stirred solution ofanhydrous oxalic acid (19 g) in anhydrous Et₂ O (600 ml). Filtration ofthe precipitated salt gave 43 g of a solid. Recrystallization of theoxalate (6.0 g) from boiling EtOH (300 ml) yielded 4.3 g (38%) ofcrystals, m.p. 182.0°-182.5°.

ANALYSIS: Calculated for C₁₉ H₂₅ NO₂.C₂ H₂ O₄ : 64.76%C; 6.99%H; 3.59%N.Found: 64.70%C; 7.02%H; 3.51%N.

EXAMPLE 30 5-Dimethylamino-2-(5-chloro-2-hydroxyphenyl)-2-phenylpentanoloxalate

A solution of3-(5-chloro-2-oxo-3-phenyl-3-dihydrobenzofuranyl)-N,N-dimethylpropylamine(23 g, 70 mmol) in anhydrous THF (100 ml) was added to a suspension ofLiAlH₄ (1.7 g, 44 mmol) in THF (200 ml) at 0°. This mixture was stirred1 hour, quenched with saturated NH₄ Cl (125 ml) and filtered. The solidswere washed with EtOAc (2×100 ml), and the combined organic phase wasseparated and reduced in vacuo. The crude diolamine was dissolved inEtOAc (350 ml), washed with 5% NaHCO₃ and saturated NaCl, dried over Na₂SO₄, and reduced in vacuo to yield 23 g of a gum. A solution of thediolamine (3.5 g) in EtOAc (50 ml) was added dropwise to a solution ofanhydrous oxalic acid (1.5 g) in Et₂ O (300 ml). Filtration of theprecipitated salt gave 3.3 g of a solid, which was recrystallized from aboiling EtOH/MeCN solution (3:2, by volume) to yield 2.5 g (56%) ofcrystals, m.p. 213.5°-214.5°.

ANALYSIS: Calculated for C₁₉ H₂₄ ClNO₂.C₂ H₂ O₄ : 59.49%C; 6.19%H;3.30%N. Found: 59.54%C; 6.23%H; 3.34%N.

EXAMPLE 31 4-Dimethylamino-2-(2-hydroxyphenyl)-2-(2-tolyl)butanolhydrochloride

A solution of2-[2-oxo-3-(2-tolyl)-3-dihydrobenzofuranyl]-N,N-dimethylethylamine (90g, 305 mmol) in anhydrous THF (400 ml) was added to a suspension ofLiAlH₄ (11.4 g, 300 mmol) in THF (850 ml) at 0°. This mixture wasstirred 1 hour, quenched with saturated NH₄ Cl (200 ml) and the organicphase decanted. The solids were washed with EtOAc (3×300 ml) anddecanted. The organic solutions were combined and evaporated in vacuo togive an oil which solidified on cooling. The crude residue was dissolvedin CH₂ Cl₂ (500 ml), washed with dilute NH₄ Cl until the pH became 8,and dried over Na₂ SO₄. A solution of the diolamine (8.4 g) in CH₂ Cl₂(60 ml) was added dropwise to an ethereal/HCl solution (1200 ml).Filtration of the precipitated salt gave 8.6 g of a solid, which wasrecrystallized from MeCN (800 ml) to yield 6.7 g (71%) of crystals, m.p.205°-207°.

ANALYSIS: Calculated for C₁₉ H₂₅ NO₂.HCl: 67.94%C; 7.82%H; 4.17%N.Found: 67.65%C; 7.88%H; 4.20%N.

EXAMPLE 32 4-Dimethylamino-2-(2-fluorophenyl)-2-(2-hydroxyphenyl)butanolhemifumarate

A solution of2-[2-oxo-3-(2-fluorophenyl)-3-dihydrobenzofuranyl]-N,N-dimethylethylamine(16.1 g, 54 mmol) in THF (50 ml) was added to a suspension of LiAlH₄(2.1 g, 54 mmol) in THF (300 ml) at 0°. This mixture was stirred 1 hour,quenched with EtOAc (60 ml), then saturated NH₄ Cl (60 ml) was added.The organic phase was decanted, the solids were washed with EtOAc, andthe organic solutions were combined and evaporated. The resultant cruderesidue was dissolved in EtOAc (300 ml), washed with dilute NH₄ Cl andsaturated NaCl, dried over Na₂ SO₄, filtered, and reduced in vacuo togive 13.9 g (85%) of a gum. A solution of the diolamine (3.2 g, 10.6mmol) in CH₂ Cl₂ (15 ml) was added to a stirred solution of fumaric acid(1.6 g, 14 mmol) in 10% ethanol/ether (300 ml). The precipitated salt(3.2 g) was filtered and dried. The crude fumarate was recrystallizedfrom 50% EtOH/MeCN (400 ml) to yield 2.15 g (48%) of crystals, m.p.220°-222°.

ANALYSIS: Calculated for C₁₈ H₂₂ FNO₂.1/2(C₄ H₄ O₄): 66.46%C; 6.71%H;3.87%N. Found: 66.10%C; 6.69%H; 3.81%N.

EXAMPLE 33 4-Dimethylamino-2-(2-hydroxyphenyl)-2-(4-tolyl)butanolhemifumarate

A solution of2-[2-oxo-3-(4-tolyl)-3-dihydrobenzofuranyl]-N,N-dimethyethylamine (8.2g, 28 mmol) in THF (35 ml) was added to a suspension of LiAlH₄ (0.7 g,17.5 mmol) in THF (100 ml) at 0°. The mixture was stirred 1 hour,quenched with saturated NH₄ Cl (30 ml), and diluted with THF (100 ml).The solids were filtered and washed with EtOAc, and the combined organicsolutions were evaporated in vacuo. The crude residue was dissolved inEtOAc (100 ml), washed with water and dilute NaCl, dried over Na₂ SO₄,filtered, and reduced in vacuo to give 6.6 g (78%) of a gum. A solutionof the diolamine (6.6 g, 22 mmol) in EtOAc (25 ml) was added to astirred solution of fumaric acid (2.9 g, 25 mmol) in 10% ethanol/ether(300 ml). The precipitated salt (6.7 g) was filtered and dried. Thecrude fumarate was recrystallized from MeOH (800 ml) to yield 3.5 g(35%) of needles, m.p. 234°-236°.

ANALYSIS: Calculated for C₁₉ H₂₅ NO₂.1/2(C₄ H₄ O₄): 70.55%C; 7.63%H;3.92%N. Found: 70.56%C; 7.57%H; 3.81%N.

We claim:
 1. A compound of the formula ##STR22## where n is 2 or 3; Xand Y are each independently hydrogen, loweralkyl or halogen, R₁ isloweralkyl, and R₂ is hydrogen, loweralkyl, cyano,beta,beta,beta-trichloroethoxyoxycarbonyl, cyclopropylmethyl, phenethylor cyanoethyl, with the proviso that when n is 2 and both X and Y arehydrogen, R₂ is not hydrogen or loweralkyl, or a pharmaceuticallyacceptable acid addition salt thereof.
 2. The compound as defined inclaim 1 where R₁ is methyl.
 3. The compound as defined in claim 2 wheren is
 2. 4. The compound as defined in claim 3 where X is hydrogen. 5.The compound as defined in claim 4 where Y is hydrogen.
 6. The compoundas defined in claim 5 where R₂ is cyano, which is2-(3-phenyl-2,3-dihydrobenzofuran-3-yl)-N-cyano-N-methylethylamine. 7.The compound as defined in claim 5 where R₂ isbeta,beta,beta-trichloroethoxyoxycarbonyl, which is2-(3-phenyl-2,3-dihydrobenzofuran-3-yl)-N-(2,2,2-trichloroethoxycarbonyl)-N-methylethylamine.8. The compound as defined in claim 5 where R₂ is cyclopropylmethyl,which is2-(3-phenyl-2,3-dihydrobenzofuran-3-yl)-N-cyclopropylmethyl-N-methylethylamine.9. The compound as defined in claim 5 where R₂ is phenethyl, which is2-(3-phenyl-2,3-dihydrobenzofuran-3-yl)-N-methyl-N-phenethylethylamine.10. The compound as defined in claim 5 where R₂ is cyanoethyl, which is2-(3-phenyl-2,3-dihydrobenzofuran-3-yl)-N-(2-cyanoethyl)-N-methylethylamine.11. The compound as defined in claim 4 where Y is 4-methyl.
 12. Thecompound as defined in claim 11 where R₂ is methyl, which is3-[3-(4-tolyl)-2,3-dihydrobenzofuran-3-yl]-N,N-dimethylethylamine. 13.The compound as defined in claim 4 where Y is 2-methyl.
 14. The compoundas defined in claim 13 where R₂ is methyl, which is3-[3-(2-tolyl)-2,3-dihydrobenzofuran-3-yl]-N,N-dimethylethylamine. 15.The compound as defined in claim 4 where Y is 2-fluoro.
 16. The compoundas defined in claim 15 where R₂ is methyl, which is3-[3-(2-fluorophenyl)-2,3-dihydrobenzofuran-3-yl]-N,N-dimethylethylamine.17. The compound as defined in claim 2 where n is
 3. 18. The compound asdefined in claim 17 where X is hydrogen.
 19. The compound as defined inclaim 18 where Y is hydrogen.
 20. The compound as defined in claim 19where R₂ is methyl, which is3-(3-phenyl-2,3-dihydrobenzofuran-3-yl)-N,N-dimethylpropylamine.
 21. Thecompound as defined in claim 19 where R₂ isbeta,beta,beta-trichloroethoxycarbonyl, which is3-(3-phenyl-2,3-dihydrobenzofuran-3-yl)-N-(2,2,2-trichloroethoxycarbonyl)-N-methylpropylamine.22. The compound as defined in claim 19 where R₂ is hydrogen, which is3-(3-phenyl-2,3-dihydrobenzofuran-3-yl)-N-methylpropylamine.
 23. Thecompound as defined in claim 19 where R₂ is phenethyl, which is3-(3-phenyl-2,3-dihydrobenzofuran-3-yl)-N-methyl-N-phenethylpropylamine24. The compound as defined in claim 19 where R₂ is cyclopropylmethyl,which is3-(3-phenyl-2,3-dihydrobenzofuran-3-yl)-N-cyclopropylmethyl-N-methylpropylamine.25. The compound as defined in claim 17 where X is 5-chloro.
 26. Thecompound as defined in claim 25 where Y is hydrogen.
 27. The compound asdefined in claim 26 where R₂ is methyl, which is3-(3-phenyl-5-chloro-2,3-dihydrobenzofuran-3-yl)-N,N-dimethylpropylamine.28. An antidepressant composition comprising an effective depressionalleviating amount of a compound of the formula ##STR23## where n is 2or 3, X and Y are each independently hydrogen, loweralkyl or halogen, R₁is loweralkyl, and R₂ is hydrogen, loweralkyl, cyano,beta,beta,beta-trichloroethoxycarbonyl, cyclopropylmethyl, phenethyl orcyanoethyl, with the proviso that when n is 2 and both X and Y arehydrogen, R₂ is not hydrogen or loweralkyl, or a pharmaceuticallyacceptable acid addition salt thereof and a carrier therefor.
 29. Ananalgesic composition comprising an effective pain alleviating amount ofa compound of the formula ##STR24## where n is 2 or 3, X and Y are eachindependently hydrogen, loweralkyl or halogen, R₁ is loweralkyl, and R₂is hydrogen, loweralkyl, cyano, beta,beta,beta-trichloroethoxycarbonyl,cyclopropylmethyl, phenethyl or cyanoethyl with the proviso that when nis 2 and both X and Y are hydrogen, R₂ is not hydrogen or loweralkyl, ora pharmaceutically acceptable acid addition salt thereof and a carriertherefor.